We hypothesize that prion diseases are a result of changes in the conformation and oligomerization state of PrPc, such that PrPc PrPsc Oligomer. The physical-chemical properties of PrPc have made it difficult to conduct experimental biophysical studies to determine the structure of this protein. We propose a series of theoretical studies to model the structure of the possible conformers of PrP. New methods for secondary structure prediction will be applied to the family of known PrP sequences. Heuristic models for secondary structure packing will be used to propose plausible tertiary structures. Peptides have been designed based on the regions of likely secondary structure in PrP. Recent experiments by our colleagues in this Program Project Grants suggest that these peptides can adopt an a-helical structure under some conditions and a beta-structure under other conditions. In fact, some of these peptides are capable of forming amyloid. We plan to use molecular dynamics calculations to stimulate the conformational behavior of these peptides. Simulations will be carried out in water and a variety of mixed solvents that could mimic the membrane environment. The results of these studies should suggest mutations that could effect the conformational preference of the peptide and perhaps the conformational preferences of the intact protein. Models of peptide aggregation will be developed from molecular dynamics simulations of two or more peptides. Again, a close correlation with experimental results from the Prusiner group will be critical to the progress of the computational effort. From the results of the peptide simulation, it may be possible to develop a useful model of the intact PrP molecule. We anticipate that alternative models will be developed and mutagenesis experiments will be designed to help sort between alternative models will be developed and mutagenesis experiments will be designed to help sort between alternative models. Insertion and deletion mutations as well as the introduction of new disulfide bridges could provide structural information that would confirm or refute the alternative model structures.